The objectives of this proposal are to examine the role of genetic risk factors, along with demographic, clinical, and radiographic factors, for intracranial hemorrhage to create a predictive model pertaining to natural history risk in patients with brain arteriovenous malformations (BAVM). We will clarify BAVM epidemiology and natural history using rigorous methodology in both cohort (longitudinal) and cross-sectional designs. Our case surveillance system identifies BAVM cases in the San Francisco Bay Area and enters them into the BAVM Registry Database at UCSF. This includes both referrals to UCSF as well as cases identified from our population-based surveillance in collaboration with KPNC (=3 million covered lives). Overlapping cases are identified. The research plan will examine the influence of genetic factors known to influence the incidence and outcome from other intracranial hemorrhage (ICH) syndromesuApolipoprotein Epsilon 2 and Epsilon 4 alleles (APOE2 and 4) and polymorphisms in genes coding for proteins in the clotting system, e.g. Factor V. We will also examine the relationship of polymorphisms in genes related to angiogenesis-related proteins. For example, mutations in the endoglin gene are associated with BAVM formation in familial syndromes; we have preliminary evidence that polymorphisms in endogtin are associated with a propensity for ICH in sporadic BAVM patients. The general hypotheses are that there are at least two clinical behaviors of BAVMs that can be separated on the basis of underlying biologic differences (high and low risk for spontaneous ICH) and that there are practical, quantifiable risk-stratifiers that can be identified. Although the primary reason to treat BAVMs is to prevent intracranial hemorrhage (ICH), treatment decisions must not only account for treatment but also natural history risk. However, data on natural history risks are currently insufficient; this greatly hampers the formulation of randomized clinical trials of BAVM treatment comparing different treatment modalities. Significance: By clearly identifying predictive genotypes for spontaneous ICH, a risk-based strategy for management can be developed for one or more multicenter clinical trials to evaluate the role of surgery, radiosurgery, endovascular therapy, and medical treatment. Such trials can better balance treatment risk against natural history risk. Physicians and surgeons would then have the means to further decrease morbidity from BAVMs and develop rational and cost-effective decision-making for interventional therapy.